Proteinases form a substantial group of biological molecules which to date constitute approximately 2% of all the gene products identified following analysis of several completed genome sequencing programmes. Proteinases have evolved to participate in an enormous range of biological processes, mediating their effect by cleavage of peptide amide bonds within the myriad of proteins found in nature. This hydrolytic action is performed by initially recognising, then binding to, particular three-dimensional electronic surfaces displayed by a protein, which align the bond for cleavage precisely within the proteinase catalytic site. Catalytic hydrolysis then commences through nucleophilic attack of the amide bond to be cleaved either via an amino acid side-chain of the proteinase itself, or through the action of a water molecule that is bound to and activated by the proteinase. Proteinases in which the attacking nucleophile is the thiol side-chain of a Cys residue are known as cysteine proteinases. The general classification of ‘cysteine proteinase’ contains many members found in a wide range of organisms from viruses, bacteria, protozoa, plants and fungi to mammals. Cathepsins S and K and indeed many other crucial mammalian proteinases belong to the papain-like CAC1 family (see Barrett, A. J et al, in ‘Handbook of Proteolytic Enzymes’, Eds. Barrett, A. J., Rawlings, N. D., and Woessner, J. F. Publ. Academic Press, 1998, for a thorough discussion).
To date, cysteine proteinases have been classified into five clans, CA, CB, CC, CD and CE (Barrett, A. J. et al, 1998). A proteinase from the tropical papaya fruit ‘papain’ forms the foundation of clan CA, which currently contains over 80 distinct and complete entries in various sequence databases, with many more expected from the current genome sequencing efforts. Proteinases of clan CA/family C1 have been implicated in a multitude of house-keeping roles and disease processes. e.g. human proteinases such as cathepsin K (osteoporosis, osteoarthritis), cathepsin S (multiple sclerosis, rheumatoid arthritis, autoimmune disorders), cathepsin L (metastases), cathepsin B (metastases, arthritis), cathepsin F (antigen processing), cathepsin V (T-cell selection), dipeptidyl peptidase I (granulocyte serine proteinase activation) or parasitic proteinases such as falcipain (malaria parasite Plasmodium falciparum) and cruzipain (Trypanosoma cruzi infection).
There currently exists a major unmet need for safe orally administered medications for the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease (COPD) and cardiovascular disease, which exhibit significant damage and remodeling of extracellular matrix (ECM). Destruction of the ECM is brought about through proteolysis of its elastin, collagen and proteoglycan constituents, which provide structure, elasticity and tensile strength to materials such as cartilage, bone, lung and vascular tissue. The proteolytic enzymes cathepsin S and cathepsin K are up-regulated under inflammatory conditions and have been implicated in the degradation of ECM components.
Cathepsins K and S are found over-expressed in rheumatoid and osteoarthritic synovium and have been shown to degrade collagen type-I and type-II, as well as aggrecan (a multidomain proteoglycan component of articular cartilage) respectively (see Hou, W. S. et al., Arthritis & rheumatism, 46 (3). 663-674, 2002; Hou, W. S. et al., Biol Chem, 384. 891-897, 2003 & Yasuda, Y. et al., Adv Drug Del Rev, 57. 973-993, 2005 and references cited herein). In addition, transgenic mice overexpressing cathepsin K, show spontaneous development of synovitis and cartilage degeneration (see Morko, J. et al., Arthritis & rheumatism, 52 (12). 3713-3717, 2005). Cathepsin S is also known to play a role in auto-antigen presentation in rheumatoid arthritis, helping prime the immune system to attack self-tissues in susceptible joints (e.g. see Podolin, P. L., et al., inflamm Res, 50:S159.2001).
As well as destruction of articular cartilage, cathepsin S and cathepsin K demonstrate potent elastinolytic activity and are involved in a broad spectrum of pathological conditions associated with elastin degradation, such as COPD and cardiovascular disease. Both enzymes are readily secreted by macrophages and smooth muscle cells and have been shown to degrade elastins from bovine aorta and lung tissue. Furthermore, in a murine model of COPD/emphysema, induced by IL-13, Cathepsin S and K were shown to be present in the diseased lung tissue and infiltrating macrophage and disease symptoms were abrogated by cysteine proteinase inhibitors (see Wolters, P. J. and Chapman, H. A., Respir Res, 1. 170-177, 2000; Novinec, M. et al., J Biol Chem, 282 (11). 7893-7902, 2007; Zheng, T. et al., J Clin Invest, 106. 1081-1093, 2000). Cathepsins S and K are also responsible for the vascular tissue damage associated with chronic cardiovascular disease and vascular injury. In murine models of atherosclerosis, Cathepsin S has been found in abundance, in atherosclerotic plaques (secreted from infiltrating macrophage) and induces plaque rupture (see Rodgers, K. J. et al., Arterioscler Thromb Vasc Biol, 26 (4):851-856, 2006). Cathepsin K and cathepsin S have been associated with vascular remodeling and causing ECM damage during the development of atherosclerosis and vascular injury-induced neointimal formation (see Cheng, X. W. et al., Am J Pathol, 164 (1). 243-251, 2004). While both enzymes are involved in the growth and rupture of abdominal aortic aaneurysms (see Abdul-Hussien, H. et al., Am J Pathol, 170 (3). 809-817, 2007).
Thus inhibition of cathepsins K and S offer an attractive approach to prevent the underlying tissue destruction which occurs in chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, COPD and cardiovascular disease.
In the prior art, the development of cysteine proteinase inhibitors for human use has recently been an area of intense activity (e.g. see Deaton, D. N. and Kumar, S., Prog. Med. Chem. 42, 245-375, 2004; Bromme, D. and Kaleta, J., Curr. Pharm. Des., 8, 1639-1658, 2002; Kim, W. and Kang, K., Expert Opin. Ther. Patents, 12 (3), 419-432, 2002; Leung-Toung, R. et al. Curr. Med. Chem., 9, 979-1002, 2002; Lecaille, F. et al., Chem. Rev., 102, 4459-4488, 2002; Hernandez, A. A. and Roush, W. R., Curr. Opin. Chem. Biol., 6, 459-465, 2002; Link, J. O. and Zipfel, S. Curr. Opin. Drug Discov. Dev., 9 (4), 471-482, 2006). Considering the CAC1 family members, particular emphasis has been placed upon the development of inhibitors of human cathepsins, primarily cathepsin K (osteoporosis) and cathepsin S (autoimmune disorders) through the use of covalent-bound but reversible peptide and peptidomimetic nitriles (e.g. see Bekkali, Y. et al, Bioorg. Med. Chem. Lett., 17 (9), 2465-2469, 2007; WO-A-07137738, WO-A-07003056), linear and cyclic peptide and peptidomimetic ketones (e.g. see Veber, D. F. and Thompson, S. K., Curr. Opin. Drug Discovery Dev., 3 (4), 362-369, 2000; WO-A-02057270, WO-A-04007501, WO-A-06064286, WO-A-05066180, WO-A-0069855), ketoheterocycles (e.g. see Palmer, J. T. et al, Bioorg. Med. Chem. Lett., 16 (11), 2909-2914, 2006, WO-A-04000838), α-ketoamides (e.g. see WO-A-06102243), cyanamides (WO-A-01077073, WO-A-01068645) and arylnitriles (e.g. see WO-A-07080191, WO-A-07039470, WO-A-06018284, WO-A-05121106, WO-A-04000843). Inhibition of CAC1 proteases by non-covalent bound compounds has been extensively described in the literature. Particular emphasis has been placed upon inhibition of cathepsin K and cathepsin S by arylaminoethylamides (e.g. see Altmann, E., et al, J. Med. Chem., 45 (12), 2352-2354, 2002; Chatterjee, A. K. et al, Bioorg. Med. Chem. Lett., 17 (10), 2899-2903, 2007; US-20050113356, US-20050107368, US-20050118568) and substituted pyrazoles or piperidines (e.g. see Wei, J., et al, Bioorg. Med. Chem. Lett., 17 (20), 5525-5528, 2007; US-2007117785, US-2003073672, WO-A-02020013).
Thus the extensive prior art describes potent in vitro inhibitors of either cathepsin S or cathepsin K and inhibitors showing efficacy in numerous animal models of disease. However, since these enzymes appear to work in tandem and both are present in many chronic inflammatory diseases, a single compound possessing dual inhibitory activity would be a distinct advantage. There are presently no human therapeutic dual inhibitors of cathepsin K and S.
Recently, Quibell, M. (WO-A-02057270) described a new motif for the general inhibition of CAC1 proteinases based upon a cis-5,5-bicyclic ketone (1).

Based upon this motif, highly potent and selective inhibitors of cathepsin K were discovered (see WO-A-0807109, WO-A-0807103, WO-A-0807130, WO-A-0807114, WO-A-0807127, WO-A-0807107, WO-A-0807112). The present inventors have now discovered a small genus of 6-(S)-chlorotetrahydrofuro[3,2-b]pyrrol-3-ones that exhibit potent dual inhibition versus human cathepsins S and K.